Bacteria are ubiquitous, and are found in virtually all habitable environments. They are common and diverse ecologically, and find unusual and common niches for survival. They are present throughout the environment, and are present in soil, dust, water, and on virtually all surfaces. Many are normal and beneficial strains, which provide a synergistic relationship with hosts. Others are not so beneficial, or cause problems along with benefits.
Pathogenic bacteria can cause infectious diseases in humans, in other animals, and also in plants. Some bacteria can only make particular hosts ill; others cause trouble in a number of hosts, depending on the host specificity of the bacteria. Diseases caused by bacteria are almost as diverse as the bacteria themselves and include food poisoning, tooth decay, anthrax, general infectious diseases, and even certain forms of cancer. These are typically the subject of the field of clinical microbiology.
Bacteria are killed in nature by bacteria-specific viruses, e.g., bacteriophage, or phage. Many phages found in nature belong to the group Caudovirales, or “tailed” phages. These viruses invariably have a single double-stranded DNA genome packaged into a proteinaceous capsid. The phage consists of three fundamental structures: the head; which in general has icosahedral symmetry, a tail structure emanating from one vertex of the icosahedral head, and 4-6 tail fibers attached to some part of the tail. It should be noted that the Order Caudoviralescontains three general morphotypes: Podoviridae (podophage), Myoviridae (myophage), and Siphoviridae (siphophage). Strictly speaking, the podophage do not have a morphogenetically separate “tail”; that is, the tail-like structure is actually assembled as part of head or capsid assembly. In the myophage and siphophage, there are separate morphogenesis pathways for heads, tails and tail fibers; all three are eventually joined together to form complete infectious virions. In podophage, there is a head pathway and a tail fiber pathway. From a functional perspective, however, the tail like structure of podophage serves the same function as the genuine tails of the other two morphotypes.
Phages kill cells by infecting, replicating, and then lysing the host cell, releasing multiple progeny virions in the process. Certain phage-derived elements are also capable of killing cells. For example, many Pseudomonas strains produce pyocins, proteinaceous components that kill other Pseudomonas strains. In general, the term “bacteriocin” is used to describe compounds produced by bacteria that kill other bacteria; bacteriocins of a wide-variety of chemical structure, from small molecules to polypeptides, are known. However, many of the pyocins were found to be “headless tails”, i.e., phage tails produced without heads or DNA. These tail-like bacteriocins kill bacteria by adsorbing to them and causing a fatal lesion in the cell envelope, although, lacking DNA, there is no replication or host lysis. Since the original discovery of the pyocins in Pseudomonas, similar tail-like bacteriocins have been identified in a wide variety of other bacteria, including both Gram-negative and Gram-positive species. See, e.g., Nakayama, et al. (2000) Mol. Microbiol. 38:213-31; Traub, et al. (1996) Zentralbl. Bakteriol. 284:124-35; Ito, et al. (1986) J. Virol. 59:103-111; Rocourt (1986) Zentralbl. Bakteriol. Mikrobiol. Hyg. 261:12-28; Shinomiya (1984) J. Virol. 49:310-14; Ishii, et al. (1965) J. Mol. Biol. 13:428-431; Daw and Falkiner (1996) Micron. 27:467-479; Strauch, et al. (2001) Appl. Environ. Microbiol. 67:5635-5642; and Abdelhamid, et al. (2002) Appl. Environ. Microbiol. 68:5704-5710. In addition, other bactericidal elements derived from phage have been described. For example, Caudovirales encode an endolysin as part of the host cell lysis functions. These enzymes degrade the host cell wall from within, leading to lysis and release of the progeny virions. Phage endolysins added exogenously to cultures or suspensions of bacteria have been shown to be capable of lysing and killing a number of Gram-positive bacteria. See, e.g., Fischetti, et al. (2005) US Pat App 20050208038 describing use of phage endolysins to kill bacteria and Takac and Blasi (2005) Antimicrob. Agents and Chemother. 49:2934-2940.
Certain bacteria are normally innocuous, but become pathogenic upon presentation of the appropriate opportunity, or become problematic upon introduction to an abnormal site or situation. Persons lacking effective immune systems are most vulnerable, and certain bacteria use susceptible weak hosts to provide a temporary environment to proliferate and disperse throughout the population.
Statistically, infectious diseases are a major medical problem. See, e.g., Watstein and Jovanovic (2003) Statistical Handbook on Infectious Diseases Greenwood, ISBN:
1573563757. In the U.S., some 40-70K deaths result from bloodstream nosocomial (hospital derived) infections each year.
Antibiotics have revolutionized clinical medicine over the last half century. Since the original discovery of antibiotic phenomenon, the mechanism of action and development of this class of remarkable therapeutic entities has made enormous progress. See, e.g., Therrien and Levesque (2000) FEMS Microbial Rev. 24:251-62; Durgess (1999) Chest 115(3 Suppl):19S-23S; Medeiros (1997) Clin. Infect. Dis. 24(Suppl 1):S19-45; Jones (1996) Am. J. Med. 100(6A):3S-12S; Ford and Hait (1993) Cytotechnology 12:171-212; and Liu (1992) Compr Ther. 18:35-42. Antibiotics had about $32B worldwide sales in 2002.
The widespread appearance of antibiotic-resistant bacteria has emphasized the vulnerability of current antimicrobial treatments to bacterial adaptation. See, e.g., Walsh (1992) Antibiotics: Actions, Origins, Resistance Amer. Soc. Microbiol., ISBN: 1555812546; Cunha (1992) Antibiotic Essentials Physicians Press, ISBN: 1890114413; Amyes (2003) Magic Bullets, Lost Horizons: The Rise and Fall of Antibiotics Taylor & Francis, ISBN: 0415272033; Axelsen (2001) Essentials of Antimicrobial Pharmacology: A Guide to Fundamentals for Practice Humana Press, ISBN: 0896038424; and Mainous and Pomeroy (eds. 2001) Management of Antimicrobials in Infectious Diseases: Impact of Antibiotic Resistance Humana Press, ISBN: 0896038211. However, many classical antibiotics require rapid replication or growth of the target bacteria to be effective.
Thus, improved methods for decreasing target bacterial growth or survival or limiting bacterial pathogenicity will find great utility. This utility may be applicable to environmental, local, topical, or particularly in vivo colonization. The present invention addresses these and other significant problems.